CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`212690Orig1s000
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`NON-CLINICAL REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
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`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
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`Indication:
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`Applicant:
`Review Division:
`Reviewer:
`Supervisor:
`Acting Division Director:
`Project Manager:
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`212690
`1, 12
`1/21/2020, 5/4/2020
`1/21/2020, 5/4/2020
`JZP-258 (calcium oxybate, potassium oxybate,
`magnesium oxybate, sodium oxybate), oral
`solution, 0.5 g/mL
`Trade name: XYWAV
`Treatment of cataplexy and excessive daytime
`sleepiness (EDS) in patients 7 years of age and
`older with narcolepsy
`Jazz Pharmaceuticals
`DN I
`Melissa Banks-Muckenfuss, PhD
`Lois Freed, PhD
`Eric Bastings, MD
`Vandna Kishore, RPh
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`Reference ID: 4621528
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`1
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`

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`NDA # 212-690
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`Reviewer: M. Banks-Muckenfuss
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`TABLE OF CONTENTS
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` 1
`
`  EXECUTIVE SUMMARY ......................................................................................... 3 
`1.1 
`INTRODUCTION .................................................................................................... 3 
`1.2 
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3 
`1.3  RECOMMENDATIONS ............................................................................................ 3 
`2  DRUG INFORMATION ............................................................................................ 3 
`2.1  DRUG ................................................................................................................. 3 
`2.2  RELEVANT INDS, NDAS, BLAS AND DMFS ........................................................... 4 
`2.3  DRUG FORMULATION ........................................................................................... 4 
`2.4  COMMENTS ON NOVEL EXCIPIENTS ....................................................................... 6 
`2.5  COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 6 
`2.6 
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 6 
`3  STUDIES SUBMITTED ............................................................................................ 6 
`3.1 
`STUDIES REVIEWED ............................................................................................. 6 
`3.3 
`PREVIOUS REVIEWS REFERENCED ........................................................................ 6 
`6  GENERAL TOXICOLOGY ....................................................................................... 7 
`11 
`INTEGRATED SUMMARY AND SAFETY EVALUATION ................................... 8 
`12 
`APPENDIX/ATTACHMENTS ............................................................................... 8 
`
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`Reference ID: 4621528
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`2
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`

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`NOA# 212-690
`
`Reviewer: M. Banks-Muckenfuss
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`1
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`Executive Summary
`
`Introduction
`1.1
`Jazz Pharmaceuticals has developed JZP-258, a mixed salt oxybate oral solution, as a
`lower sodium alternative to Xyrem® sodium oxybate oral solution for the treatment of
`cataplexy or excessive daytime sleepiness (EDS) in pediatric (7 years of age and older)
`and adult patients with narcolepsy. Xyrem contains 1.638 g of sodium per 9 g dose,
`while JZP-258 contains 131 mg of sodium, 642 mg of potassium, 687 mg of calcium,
`and 182 mg of magnesium per 9 g dose.
`
`1.2 Brief Discussion of Nonclinical Findings
`This NOA is primarily supported by cross-reference to the nonclinical pharmacology, PK,
`and toxicology sections of NOA 21-196 for Xyrem (sodium oxybate; Jazz Pharmaceuticals).
`The sponsor submitted a PK study, a dose-ranging toxicity study, and a GLP 3-month
`bridging toxicity study of JZP-258 by oral administration in dogs (see the nonclinical
`reviews under IND 49641, dated June 02, 2014 and January 28, 2017). Generally, the
`toxicities observed with JZP-258 were comparable to those observed with sodium
`oxybate (see original Xyrem review by Dr. Rosloff, dated February 2, 2001 ).
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`1.3 Recommendations
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`1.3.1 Approvability
`There is no objection to the approval of NOA 212-690 for JZP-258 for the treatment of
`EDS or cataplexy in narcolepsy in adults and children 7 years and older.
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`1.3.3 Labeling
`The nonclinical sections of the current Xyrem labeling should be utilized for JZP-258.
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`2
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`Drug Information
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`2.1
`Drug
`Generic Name:
`
`Code Name
`Chemical Name
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`Calcium oxybate, potassium oxybate,
`magnesium oxybate, sodium oxybate
`JZP-258
`Calcium, potassium, magnesium and sodium
`salts of 4-hydroxybutanoic acid.
`
`Molecular Formula/Molecular Weight
`
`oxybate is C4Ha0 3, with MW= 104. 1 g/mol
`[from the sponsor's submission, below]
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`Reference ID 4621528
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`3
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`

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`NDA # 212-690
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`Reviewer: M. Banks-Muckenfuss
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`
`Structure or Biochemical Description
`
`[from the sponsor’s submission, below]
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`
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`
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`Pharmacologic Class
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`2.2 Relevant INDs, NDAs, BLAs and DMFs
`IND 49,641
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`sodium oxybate
`NDA 21-196
`sodium oxybate, Xyrem
`2.3 Drug Formulation
`JZP-258 is a mixed (sodium, potassium, calcium, and magnesium) salt oral solution;
`see the sponsor’s Table 1, below. The concentration of the oxybate active moiety is
`identical for Xyrem and JZP-258; both contain 0.413 g/mL oxybate (4-hydroxybutanoic
`acid).
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`Central Nervous System (CNS) depressant
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`The sponsor stated that the amount of each cation in the maximum recommended daily
`dose (i.e., 9 g/ night in adults, and up to 9 g/ night in children on a weight basis) is within
`the US dietary intake guidelines for adults (see the sponsor’s Table 2, below).
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`Reference ID: 4621528
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`4
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`NDA # 212-690
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`
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`Reviewer: M. Banks-Muckenfuss
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`
`
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`The amounts of each cation in Table 2 are also within the US dietary guidelines for
`children, except for magnesium in the youngest children (i.e., 7 to 8 year olds). The
`recommended daily allowance (RDA) for magnesium is 130 mg in children 4 to 8 years
`old. However, the weight-based dosing for a 7 to 8 year old child (i.e., average weight
`of approximately 20 to 30 kg; see the sponsor’s Table 3, below) would contain
`approximately 121 mg of magnesium at the maximum recommended dose of 6 g. The
`tolerable upper limit for magnesium, based on magnesium from non-food sources, is 5
`mg/kg or 110 mg for children 4-8 years of age (NIH Magnesium Fact Sheet for Health
`Professionals, March 24, 2020). As noted by the sponsor, intake of excess magnesium
`generally results in diarrhea, which is monitorable.
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`Reference ID: 4621528
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`5
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`NOA# 212-690
`
`Reviewer: M. Banks-Muckenfuss
`
`Rttomm t'ndt'd Initial JZP-258 Do'iagt' for P atit'nts 7 Yt'ars of . .\gt' and Oldt'r
`~lu:imum Wttkl~- Dosagt
`~fa:rimum RKommtndtd
`lncrtast
`Initial Dosagt
`Do~agt
`Takt 1.5 to
`Takt 2.5 to
`Takt 2.5 to
`.. Hours
`Takr at
`4 Hours
`4 Hours
`Takt at
`Takt at
`L·u rr:
`Brdtimr:
`Lattr:
`Brd timr:
`Latrr:
`Brdtimr:
`There i> insufficient infonnation to pro\1de specific dosing recommendatiom for patients who
`weigh less than 20 kg.
`o.s g
`0.5 g
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`3g
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`3g
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`~ lg
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`< I f¥
`-
`Q
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`Tnblt' 3:
`
`Patirnt
`Wright
`< 20 kg'
`
`20 kg 10
`~ 30kg
`30 kg to
`< 45 kg
`~45 kg
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`~ 1.5 g
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`::: Ug
`
`0.5 g
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`0.5 g
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`3.75 g
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`::: 2.25g
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`::: 2.25 g
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`0.75 g
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`0.15 g
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`-l.5 g
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`3.15 g
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`.t) g
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`JZJ>-25& may be giv en at bednme or after ;m mifu.l penod of !:l.eep.
`• If JZP-258 is med mpatients 7 )"t!.llS of age and older v.ilo weigh !e.s than 20 kg. a lower stariine;~age, lower
`ma.'O!Dllll v.~· clcr..age in.ere~. and lov.w total ma.'Cimum nightly dosa,,,<>e ~bould be constdered.
`Xote.: Unequal dmagoes may be raquired for 50IDl! pa1lenti to achm't' opamal trertment
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`2.4 Comments on Novel Excipients
`
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`>14! and rCb><41% water.
`
`(b)(4J
`JZP-258 is formulated as <bll41% drug substance with r(b><41% (w/w) sucralose
`- - - - -
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`2.5 Comments on lmpurities/Degradants of Concern
`The impurity profile and limits for the JZP-258 drug substance were identified as the
`same as those for Xyrem.
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`2.6 Proposed Clinical Population and Dosing Regimen
`JZP-258 is being developed for the same indication and patient populations as Xyrem
`(i.e., the treatment of cataplexy or EDS in patients 7 years of age and older with
`narcolepsy). See the sponsor's dosing table in Drug Formulation, above.
`
`3
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`Studies Submitted
`
`3.1 Studies Reviewed
`None.
`
`3.3 Previous Reviews Referenced
`Nonclinical review for NOA 21-196, Barry Rosloff, PhD, February 2, 2001
`Nonclinical review for NOA 21-196, Supplement 30, Melissa Banks-Muckenfuss, PhD
`October 24, 2018
`Nonclinical reviews under IND 49641 , June 2, 2014 and January 28, 2017
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`Reference ID 4621528
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`6
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`

`
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`Reviewer: M. Banks-Muckenfuss
`
`NDA # 212-690
`
`6 General Toxicology
`The sponsor conducted non-GLP dose-ranging toxicity (MTD-estimating) and PK
`studies, and a GLP bridging toxicity studies in beagle dogs. These studies were
`previously reviewed and are briefly summarized below.
`
`In a non-GLP oral MTD dose-ranging toxicity study in dogs (study 1301-007; see P/T
`review dated 6/2/14), an acute dose of 600 mg/kg JZP-258 was determined to be an
`MTD. JZP-258 (0, 150, 350, and 600 mg/kg) was orally administered for 7 days
`(N=2/sex/group) in the repeated dose phase. Body weight losses (4-14%) were
`observed, as were hematological alterations (e.g., ~10% reductions in hemoglobin and
`hematocrit in MD and HD males).
`
`In the PK study, the sponsor tested single oral gavage doses of 0, 75, and 150 mg/kg
`JZP-258 or Xyrem in male and female dogs. Systemic exposures were similar after
`administration of JZP-258 or Xyrem; see the sponsor’s summary Table 1, below.
`
`
`
`
` A
`
` 3-month GLP bridging toxicity study in dogs (Study 1301-009) was conducted testing
`oral doses of 0, 300, 600, 1000 (500 mg/kg BID) JZP-258 as well as 600 mg/kg sodium
`oxybate (Xyrem). Generally, the toxicities demonstrated with sodium oxybate and JZP-
`258 appeared similar. CNS signs occurred (e.g., head shaking) in one HD JZP-258
`male that appeared Cmax-related based on timing. Dose-dependent abnormal
`salivation was reported, as well as altered feces and emesis. Mild hematological
`alterations (i.e., slight RBC parameters reductions) that had previously been observed
`in the dose-ranging study were also observed in the bridging study. Glandular atrophy
`was observed in several organs (e.g., salivary glands, GI tract), which was also noted to
`have occurred in the original dog toxicity studies for Xyrem (see Dr. Rosloff’s review of
`Xyrem, dated 2/2/01). It is noted that atrophy of the submucosal glands of the stomach
`(pyloric, glandular) were of minimal severity in the LD and MD JZP-258-dosed animals
`as well as Xyrem-dosed animals and mild severity in the HD JZP-258 -dosed animals;
`this change was not reported in the original Xyrem study. Although difficult to assess
`based on the number of animals used in nonrodent studies, the severity of the glandular
`atrophy may have been slightly increased with the JZP-258. The pathologist indicated
`
`Reference ID: 4621528
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`7
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`

`
`
`Reviewer: M. Banks-Muckenfuss
`
`NDA # 212-690
`
`that the histopathological alterations generally correlated with increased salivation
`(particularly in males), which appeared to resolve during the 2-week recovery period
`(the glandular atrophy did not show resolution). The toxicological importance of the
`minimal mineralization of the ovary that occurred in 2 HDF was unclear, and no similar
`finding was reported in recovery animals. The NOAELs were 600 mg/kg/day for JZP-
`258 and sodium oxybate (Xyrem) for 91 days. The small safety margin for adverse
`CNS effects (noted in a single male, ~3-fold) was not an unexpected toxicity for the
`oxybate active moiety.
`
`Integrated Summary and Safety Evaluation
`11
`The sponsor has developed JZP-258 (mixed oxybate salts) as a lower sodium
`alternative to Xyrem (sodium oxybate) for the treatment of cataplexy or EDS in
`narcolepsy; oxybate (4-hydroxybutanoic acid) is the active moiety in both formulations.
`This NDA is primarily supported by cross-reference to the nonclinical pharmacology,
`PK, and toxicology sections of NDA 21-196 for Xyrem (sodium oxybate; Jazz
`Pharmaceuticals). Xyrem was recently approved for the treatment of cataplexy or EDS
`in pediatric patients (7 years and older) with narcolepsy in 2018.
`
`12 Appendix/Attachments
`References
`Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine (US)
`Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC,
`Taylor CL, Yaktine AL et al., editors. Washington (DC): National Academies Press (US);
`2011.
`
`Reference ID: 4621528
`
`8
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`

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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
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`/s/
`------------------------------------------------------------
`
`MELISSA K BANKS-MUCKENFUSS
`06/08/2020 10:55:21 PM
`
`LOIS M FREED
`06/09/2020 03:12:06 PM
`I concur.
`
`Reference ID: 4621528
`
`